title: Novel quinolinylaminoisoquinoline bioisosteres of sorafenib as selective RAF1 kinase inhibitors: design, synthesis, and antiproliferative activity against melanoma cell line.
abstract: Design and synthesis of a new series of quinolinylaminoisoquinoline derivatives as conformationally restricted bioisosteres of Sorafenib are described. Their in vitro antiproliferative activity against A375P melanoma cell line was tested. Compounds 1b, 1d, 1g, and 1j showed the highest potency against A375P cell line with IC50 values in sub-micromolar scale. In addition, compound 1d exerted high selectivity towards RAF1 serine/threonine kinase with 96.47% inhibition at 10 µM, and IC50 of 0.96 µM. This compound can possess antiproliferative activity against melanoma cells through inhibition of RAF1 kinase.
authors.affiliation: Chemical Kinomics Research Center, Korea Institute of Science and Technology, Cheongryang, Seoul 130–650, Republic of Korea.
authors.forename: Hye Jung
authors.initials: HJ
authors.lastname: Cho
authors.forename: Mohammed Ibrahim
authors.initials: MI
authors.lastname: El-Gamal
authors.forename: Chang-Hyun
authors.initials: CH
authors.lastname: Oh
authors.forename: So Ha
authors.initials: SH
authors.lastname: Lee
authors.forename: Taebo
authors.initials: T
authors.lastname: Sim
authors.forename: Garam
authors.initials: G
authors.lastname: Kim
authors.forename: Hong Seok
authors.initials: HS
authors.lastname: Choi
authors.forename: Jung Hoon
authors.initials: JH
authors.lastname: Choi
authors.forename: Kyung Ho
authors.initials: KH
authors.lastname: Yoo
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015195:Drug Design; D006801:Humans; D007546:Isoquinolines / Q000737:chemistry*; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000737:chemistry; D010671:Phenylurea Compounds / Q000737:chemistry*; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000633:toxicity; D019908:Proto-Oncogene Proteins c-raf / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000077157:Sorafenib; D013329:Structure-Activity Relationship
chemical_list: D007546:Isoquinolines; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D009536:Niacinamide; D000077157:Sorafenib; D019908:Proto-Oncogene Proteins c-raf; C039109:isoquinoline